WO2017210130A1 - Compositions and methods of using nintedanib for improving glaucoma surgery success - Google Patents

Compositions and methods of using nintedanib for improving glaucoma surgery success Download PDF

Info

Publication number
WO2017210130A1
WO2017210130A1 PCT/US2017/034792 US2017034792W WO2017210130A1 WO 2017210130 A1 WO2017210130 A1 WO 2017210130A1 US 2017034792 W US2017034792 W US 2017034792W WO 2017210130 A1 WO2017210130 A1 WO 2017210130A1
Authority
WO
WIPO (PCT)
Prior art keywords
nintedanib
surgery
days
ocular
glaucoma
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2017/034792
Other languages
French (fr)
Inventor
Jinsong Ni
Rong Yang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cloudbreak Therapeutics LLC
Original Assignee
Cloudbreak Therapeutics LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=60477780&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2017210130(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to KR1020247011786A priority Critical patent/KR20240052865A/en
Priority to CN201780029923.1A priority patent/CN109561985B/en
Priority to CA3025325A priority patent/CA3025325A1/en
Priority to MX2018014868A priority patent/MX2018014868A/en
Priority to JP2019515766A priority patent/JP7079243B2/en
Priority to AU2017274195A priority patent/AU2017274195B2/en
Application filed by Cloudbreak Therapeutics LLC filed Critical Cloudbreak Therapeutics LLC
Priority to EP17807295.5A priority patent/EP3463225B1/en
Priority to BR112018074450-6A priority patent/BR112018074450A2/en
Priority to KR1020187037794A priority patent/KR102496234B1/en
Priority to KR1020237003530A priority patent/KR102657707B1/en
Publication of WO2017210130A1 publication Critical patent/WO2017210130A1/en
Priority to US16/131,945 priority patent/US10335408B2/en
Anticipated expiration legal-status Critical
Priority to US16/439,469 priority patent/US10688092B2/en
Priority to AU2022204216A priority patent/AU2022204216B2/en
Priority to AU2025200273A priority patent/AU2025200273A1/en
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A61K9/0051—Ocular inserts or implants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present disclosure relates to ocular compositions comprising nintedanib and methods of use thereof for improving the success rate of glaucoma surgery.
  • Glaucoma refers to a group of eye conditions that damage the optic nerve, which is often caused by an abnormally high pressure in the eye.
  • One way to reduce pressure in an eye with glaucoma is to surgically create a drain in the eye. This type of surgery is called a glaucoma filtration surgery, e.g., trabeculectomy.
  • a piece of tissue in the drainage angle of the eye is removed, creating an opening. This new opening creates a drain, allowing fluid to drain out of the eye.
  • the eye pressure is reduced because fluid can now drain with relative ease through the new opening through the new opening into a reservoir (bleb) underneath the conjunctiva. The fluid is then absorbed by the body.
  • the disclosure provides a method for improving the success rate of glaucoma surgery (e.g., glaucoma filtration surgery) by administering nintedanib to the eye of a subject in need of such treatment.
  • a method for adjunctive treatment associated with glaucoma filtration surgery in a subject comprising administering to a subject in need thereof an effective amount of a composition comprising nintedanib or a pharmaceutically acceptable salt thereof. The method improves the success rate of glaucoma surgery.
  • Glaucoma surgery includes, for example, the classic trabeculectomy method, or a method selected from the group consisting of Trabectome, Gonioscopy-assisted transluminal trabeculectomy, Excimer laser trabeculostomy, and Endoscopic cyclophotocoagulation.
  • the glaucoma surgery performed may also be for implantation of an ocular filtration device, wherein the ocular filtration device is an ocular stent.
  • the ocular filtration device may be selected from the group consisting of an iStent, Hydrus and CyPass microstent.
  • the amount of nintedanib administered to the subject is effective to extend the duration of lower IOP, increase either the absolute success rate or the qualified success rate for at least 10 days, at least 90 days, at least 365 days, at least 750 days, or at least 3650 days following surgery; or wherein the amount of nintedanib administered is effective to prolong bleb survival.
  • the nintedanib composition is administered in the form of topical ocular formulation (e.g., a topical eye drop) or implant.
  • the nintedanib is in a topical ocular formulation administered topically to the affected eye.
  • the concentration of nintedanib in the formulation is from 0.001 % to 10% by weight or by volume the total amount of composition.
  • the topical ocular formulation is a solution, a suspension or an emulsion.
  • nintedanib is in an implant or semi-solid sustained release formulation injected into the affected eye.
  • the amount of nintedanib in the implant is from 1 ⁇ g to 100 mg.
  • the disclosed methods are performed by the combination of nintedanib and an antimetabolite drug.
  • the antimetabolite drug can be, but not limited to, Mitomycin C, 5-Fluorouracil, Floxuridine, Cytarabine, 6-Azauracil, Azathioprine, Methotrexate, Mycophenolate Mofetil, and Thiotepa.
  • the disclosed methods reduce scar formation in glaucoma surgery by attenuating abnormal vascularity and fibrosis at the surgical site.
  • the disclosed methods are performed before operation, in conjunction with operation or after operation, to reduce failure in glaucoma surgery.
  • the amount of nintedanib administered is effective to reduce scar formation at the site of the surgery;
  • the amount nintedanib administered is effective to extend the duration of lower IOP for at least 10 days, at least 365 days, or at least 3650 days following surgery.
  • the amount of nintedanib administered is effective to prolong bleb survival
  • one or more includes at least one, more suitably, one, two, three, four, five, ten, twenty, fifty, one-hundred, five-hundred, etc., of the item to which "one or more" refers
  • subject refers to an animal or human, or to one or more cells derived from an animal or human.
  • the subject is a human.
  • Subjects can also include non-human primates.
  • a human subject can be known as a patient.
  • Figure 1 is a flow chart demonstrating an exemplary mechanism to reduce excess scar formation and to improve the success rate of glaucoma surgery.
  • Figure 2 is a graph showing bleb survival following glaucoma filtration surgery in a rabbit model.
  • Figure 3 is a graph showing intraocular pressure (IOP) following glaucoma filtration surgery in a rabbit model.
  • Figure 4 is a graph showing absolute success of glaucoma filtration surgery in a clinical study according to the methods disclosed herein.
  • Glaucoma is a group of diseases that are characterized by the death of retinal ganglion cells ("RGCs”), specific visual field loss, and optic nerve atrophy.
  • RRCs retinal ganglion cells
  • Glaucoma is a leading cause of blindness in the world.
  • a variety of treatment options, effective to reduce intraocular pressure (“IOP"), are available to control, and, perhaps, to slow, the progression of the disease.
  • Treatment options include, for example, pharmaceutical therapy (i.e., IOP-lowering drugs), laser eye surgery, and/or conventional surgical methods, such as glaucoma filtration surgery (or also known as filtering surgery or trabeculectomy).
  • Glaucoma surgery is still commonly practiced in other parts of the world, especially for closed-angle glaucoma.
  • Glaucoma surgery has the advantage of low cost over time and doesn't have to deal with compliance issues associated with topical eye drops that need multiple applications per day.
  • the traditional glaucoma filtration surgery and trabeculectomy have high failure rate (Schlunck et al. Exp Eye Res. 2016; 142:76-82) and methods of implanting an ocular filtration device, e.g., a glaucoma drainage device, also have long term failure problems (Amoozgar et al. Curr Opin Ophthalmol. 2016;27(2): 164-9).
  • the failures are due to excessive postoperative wound healing with subsequent fibrosis and scar formation that obstruct drainage.
  • the damage to tissue by surgery often induces pro-inflammation and pro-fibrogenic factors that lead to abnormal extracellular matrix change and fibrosis.
  • Myofibroblast hyper-proliferation induced by these factors subsequently causes excessive fibrosis and scar formation.
  • the antimetabolite drug Mitomycin C (MMC) has been administered during or after glaucoma surgery as an anti-scaring agent.
  • Another antimetabolite drug is also used mainly by local injection during follow-up (Schlunck et al. Exp Eye Res. 2016; 142:76-82).
  • 5- fluorouracil 5-FU
  • These antimetabolite drugs work by blocking fast proliferating fibroblasts. Their activities are not selective and are known to cause side effects.
  • the anti-cell division activity sometimes causes bleb leakage post-surgery. Better postoperative management of glaucoma surgery is still an unmet medical need.
  • the present disclosure improves glaucoma surgery success by administering to the eye a composition with the following key attributes: 1) the composition will inhibit several important pathological pathways simultaneously and these pathways are disclosed below; 2) the composition utilizes small molecule drug(s) as opposed to antibody drugs to achieve more efficient drug delivery to the target tissue; 3) the composition is a topical formulation in the form of either an eye drop or implant for convenient and consistent drug delivery to the site of surgery; and 4) the composition contains nintedanib, which can be used in combination with an antimetabolite drug to achieve additive or synergistic effect in improving the success of glaucoma filtration surgery.
  • the disclosure provides a method of using a topical formulation (e.g., topical eye drop, implant) comprising nintedanib, before, during or after surgery.
  • Nintedanib meets the requirement of inhibiting vascular endothelial growth factor (“VEGF”) receptors (“VEGFR”) 1 -3, platelet-derived growth factor receptor (“PDGFR”) -a and - ⁇ and fibroblast growth factor receptor 2 (“FGFR2”) to achieve the needed efficacy.
  • VEGF vascular endothelial growth factor
  • VDGFR vascular endothelial growth factor receptors
  • PDGFR platelet-derived growth factor receptor
  • FGFR2 fibroblast growth factor receptor 2
  • PIGF placental growth factor
  • Figure 1 The mechanism for improving glaucoma surgery success rate provided by the present disclosure is summarized in Figure 1, which shows that nintedanib, in a suitable ocular formulation, would simultaneously block signal pathways of the key pathogenic factors involved in excess wound healing, including PIGF, VEGF, PDGF, FGF, and would enhance the success of glaucoma surgery by reducing scar formation.
  • the term "improving glaucoma surgery success” means extending the duration of reduced (i.e., lower) IOP for a period of at least 10 days, at least 90 days, at least 365 days, at least 750 days, or at least 3650 days) following surgery, an increase of IOP-reduction percentage comparing to the pre-surgical baseline over a given period of time (e.g., at least 10 days, at least 90 days, at least 365 days, at least 750 days, or at least 3650 days) after surgery, increase of the absolute (also known as complete) success rate (defined as percent of patients kept within normal IOP range with reduced IOP in relation to the baseline without any glaucoma medication) over a given period of time, increase of qualified success rate (defined as percent of patients kept within normal IOP range with reduced IOP in relation to the baseline with the help of glaucoma medications) over certain period of time (e.g., at least 10 days, at least 90 days, at least 365 days, at least 750 days, or
  • normal IOP or “normal IOP range” refers to intraocular pressure in the human eye of between about 5 mm Hg to about 22 mm Hg, or about 10 mm Hg to about 21 mm Hg.
  • treatment used herein to generally refer to obtaining a desired pharmacologic and/or physiologic effect.
  • the effect can be prophylactic in terms of completely or partially preventing a disease or symptom(s) thereof and/or may be therapeutic in terms of a partial or complete stabilization or cure for a disease and/or adverse effect attributable to the disease.
  • treatment encompasses any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing the disease and/or symptom(s) from occurring in a subject who may be predisposed to the disease or symptom but has not yet been diagnosed as having it; (b) inhibiting the disease and/or symptom(s), i.e., arresting their development; or (c) relieving the disease symptom(s), i.e., causing regression of the disease and/or symptom(s).
  • Those in need of treatment include those already inflicted (e.g., those with high IOP, those with an infection, etc.) as well as those in which prevention is desired (e.g., those with increased susceptibility to glaucoma, those suspected of having high IOP, etc.).
  • Nintedanib ⁇ Methyl (3Z)-3- ⁇ [(4- ⁇ methyl[(4-methylpiperazin-l-yl) acetyl] amino ⁇ phenyl)amino] (phenyl)methylidene ⁇ -2-oxo-2,3-dihydro-lH-indole-6- carboxylate ⁇ is a kinase inhibitor as described herein.
  • Nintedanib inhibits primarily receptor tyrosine kinases including, for example vascular endothelial growth factor receptor (VEGFR 1-3), platelet-derived growth factor receptor (PDGFR a and ⁇ ), fibroblast growth factor receptor (FGFR 1-4).
  • VEGFR 1-3 vascular endothelial growth factor receptor
  • PDGFR a and ⁇ platelet-derived growth factor receptor
  • FGFR 1-4 fibroblast growth factor receptor
  • compositions which include compounds identified by a method described herein as active ingredients. Also included are the pharmaceutical compositions themselves.
  • compositions typically include pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipient or “pharmaceutically acceptable carrier” includes saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
  • phrases "pharmaceutically acceptable salt” as used herein means those salts of a compound of interest that are safe and effective for administration to a mammal and that possess the desired biological activity.
  • Pharmaceutically acceptable acid salts include, but are not limited to hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, I 0 isonicotinate, carbonate, bicarbonate, acetate, lactate, salicylate, citrate, tartrate, propionate, butyrate, pyruvate, oxalate, malonate, pantothenate, bitartarte, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, thanesulfonate, benzenesulfonate, p-toluenesulfonate
  • solutions, suspensions, , creams, ointments, Gels, gel-forming liquid, suspension containing liposomes or micelles, spray orformulation, or emulsions used for ophthalmic application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents; antioxidants; chelating agents; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • compositions suitable for injectable use can include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. It should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying, which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the therapeutic compounds are prepared with carriers that will protect the therapeutic compounds against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polygly colic acid, collagen, polyorthoesters, and polylactic acid.
  • Such formulations can be prepared using standard techniques, or obtained commercially.
  • the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.
  • compositions and formulations of nintedanib can be administered topically (e.g., as a topical ocular formulation) or as an injection of semi-solid formulation or solid implant, or by any other suitable methods known in the art. While it is possible to use the agent disclosed herein for therapy as is, it may be preferable to administer the agent as a pharmaceutical formulation, e.g., in admixture with a suitable pharmaceutical excipient, diluent, or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • Pharmaceutical formulations include at least one active compound, in association with a pharmaceutically acceptable excipient, diluent, and/or carrier.
  • the pharmaceutical composition disclosed herein may include a
  • therapeutically effective amount of an agent described herein. Such effective amounts can be determined based on the effect of the administered agent, or the combinatorial effect of agents if more than one agent is used. A therapeutically effective amount of an agent may also vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the compound to elicit a desired response in the individual, e.g., amelioration of at least one disorder parameter or amelioration of at least one symptom of the disorder. A therapeutically effective amount is also one in which any toxic or detrimental effects of the composition are outweighed by the therapeutically beneficial effects.
  • Effective doses of the compositions of the present disclosure, for the treatment of conditions vary depending upon many different factors, including means of administration, target site, physiological state of the subject, whether the subject is human or an animal, other medications administered, and whether treatment is prophylactic or therapeutic. Treatment dosages can be titrated using routine methods known to those of skill in the art to optimize safety and efficacy.
  • the topical ocular formulation is a solution, a suspension, , creams, ointments, gels, gel-forming liquid, suspension containing liposomes or micelles, spray formulation, or an emulsion.
  • the topical ocular formulation also includes one or more pharmaceutically acceptable excipients selected from stabilizers, surfactants, polymer base carriers, gelling agents, organic co-solvents, pH active components, osmotic active components and with or without preservatives.
  • the sustained release semi-solid formulation, sustained release solid formulation or ocular implant is injected into the affected eye.
  • the sustained release semi-solid formulation, sustained release solid formulation or ocular implant further comprises a pharmaceutically acceptable excipient.
  • the sustained release semi-solid formulation, sustained release solid formulation or ocular implant includes a multikinase inhibitor, the antimetabolite, or combination thereof; and a biodegradable polymer selected from polylactic acid (PLA), poly gly colic acid (PLGA) and polylactic acid poly gly colic acid copolymers.
  • a biodegradable polymer selected from polylactic acid (PLA), poly gly colic acid (PLGA) and polylactic acid poly gly colic acid copolymers.
  • Administration of a composition or formulation can be once a day, twice a day, three times a day, four times a day or more often. Frequency may be decreased during a treatment maintenance phase of the treatment, e.g., once every second or third day instead of every day or twice a day.
  • the dose and the administration frequency can be adjusted based on the judgment of the treating physician, for example, taking into account the clinical signs, pathological signs and clinical and subclinical symptoms of a disease of the conditions treated with the present methods, as well as the patient's clinical history.
  • compositions will typically contain an effective amount of nintedanib. Preliminary doses can be determined according to animal tests, and the scaling of dosages for human administration can be performed according to art-accepted practices.
  • Length of treatment i.e., number of days
  • the number of days of treatment may range from about 1 day to about 365 days.
  • the efficacy of treatment can be monitored during the course of treatment to determine whether the treatment has been successful, or whether additional (or modified) treatment is necessary.
  • Dosage, toxicity and therapeutic efficacy of the therapeutic compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • Dosage forms for nintedanib can be readily determined by the ordinarily skilled artisan, and can e.g., be obtained in animal models and in clinical studies reported in the literatures, for determining dosage, safety and efficacy according to standard methods known in the art. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition.
  • compositions for use in the present methods may include nintedanib at a concentration of 0.001% to 10% by weight or by volume the total amount of composition.
  • nintedanib at a concentration of 0.001% to 10% by weight or by volume the total amount of composition.
  • an aqueous composition comprises 0.001%, 0.01%, 0.1%, 0.5%, 1.0%, 1.5%, 2.0%, 5.0% or up to 10% nintedanib.
  • administration to the eye of an aqueous solution may be in the form of "drop" or number of drops (e.g. of nintedanib solution) from a dropper or pipette or other dedicated sterile devices.
  • drops e.g. of nintedanib solution
  • Such drops will typically be up to 50 microliters in volume, but maybe smaller e.g. less than 10 microliters.
  • the rabbit glaucoma surgery model is used to illustrate use of the presently disclosed methods for improving the success of glaucoma filtration surgery.
  • an established rabbit model of glaucoma filtration surgery would be used to study the effects of nintedanib 0.2% solution on the wound-healing events after surgery.
  • the surgical procedure is as described in Wong et al. (Wong et al. Invest Ophthalmol Vis Sci. 2003; 44(3): 1097-1103). Briefly, a partial thickness 8-0 silk corneal traction suture is placed superiorly, and the eye pulled down.
  • a fornix based conjunctival flap is raised, after which a blunt dissection of the subconjunctival space is performed of approximately 5 mm along the limbus and 8 mm posteriorly.
  • a microvitreoretinal (MVR) blade is used to make a partial-thickness scleral incision 3 to 4 mm behind the limbus, and a scleral tunnel to the corneal stroma is fashioned.
  • a 22 -gauge, 25 -mm intravenous cannula (Venflon 2; Beckton Dickinson, Oxford, UK) is passed through a scleral tunnel anteriorly until the cannula needle is visible in the clear cornea.
  • Entry into the anterior chamber is made with a cannular needle, which is then withdrawn as the cannula is advanced to the mid-pupillary area.
  • the cannula is trimmed and beveled at its scleral end so that it protrudes 1 mm from the insertion point, and a 10-0 nylon suture is placed to fix the tube to the scleral surface.
  • the conjunctival incision is closed with two interrupted sutures and a central, mattress-type 10-0 nylon suture attached to a needle (B/V 100-4; Ethicon) to give a water-tight closure.
  • One drop each of guttae chloramphenicol and Betnesol-N (Glaxo Wellcome, Uxbridge, UK) ointment is instilled at the end of surgery.
  • Glaucoma surgery would be performed on the left eye as described. After surgery, the rabbits would be arranged into two groups and one group would be treated with vehicle and another with nintedanib 0.2% solution. Treatments would begin immediately after surgery and the treatment would be TID for 2 weeks. The survival of the bleb formed by the surgery and the intraocular pressure (IOP) would be followed for 28 days. Histological analysis of the scar tissue would be performed at the end of the study.
  • IOP intraocular pressure
  • FIG. 2 provides a graph showing the survival curve of the bleb after surgery. As shown in Figure 2, the nintedanib group would show a substantially prolonged bleb survival comparing to the vehicle group. By the end of study on day 28, no bleb would survive in the vehicle group while most of the bleb would survive in the nintedanib group.
  • Figure 3 is a graph showing the IOP curve during the follow up period after the surgery. IOP remained low (i.e., below 20 mm- » -in the nintedanib group and increased gradually in the vehicle group. The difference would be statistically significant. In addition to bleb survival and IOP change, histological analysis of scar tissue at the surgical site would show less scar tissue in the nintedanib group than the vehicle group.
  • nintedanib 0.2% solution increases the success of glaucoma surgery (i.e., prolonged bleb survival, extended duration of lower IOP following surgery and/or reduced fibrosis/scarring).
  • Example 2 Topical Ocular Formulations of Nintedanib as Adjunct Therapy to Glaucoma Filtration Surgery Topical nintedanib 0.2% as adjunct therapy to increase success of
  • Vandewalle et al (Vandewalle et al. Br J Ophthalmol. 2014, Jan; 98(l):73-8).
  • Patients with medically uncontrolled open-angle glaucoma scheduled for a primary trabeculectomy would be enrolled and randomized to receive one drop TID of either nintedanib or placebo solutions. The treatment would start immediately after surgery and would last for a month. Approximately 150 patients would be enrolled in the study.
  • IOP insulin pressure
  • Goldmann applanation tonometry Two measurements were taken by masked observers and averaged to determine the mean IOP if two values were within 2 mm Hg. A third measurement would be taken if the difference between the first two determinations is >2 mm Hg.
  • Patients would be examined on day 1; at weeks 1, 2, and 4; and at months 3, 6, and 12 after trabeculectomy. All patients would go through a comprehensive ophthalmic examination that included measurements of best-corrected visual acuity, slit-lamp examination including a Seidel test, IOP measurement, and fundus biomicroscopy with a 90-diopter lens. The number of postoperative IOP-lowering medications, intra- and postoperative complications, and surgical interventions would also be recorded.
  • Absolute success would be the primary endpoint and is defined as intraocular pressure (IOP) ⁇ 21 mm Hg and >5 mm Hg with at least 20% reduction from baseline and no loss of light perception.
  • IOP intraocular pressure
  • the drug product is an isotonic ophthalmic solution prepared in 2-hydroxypropyl beta cyclodextrin or other similar cyclodextrins, and buffer solution, pH range from 5.5 to 8.0. Other viscosity, lubricant, preservative agents might be added to enhance functionality of the formulation.
  • the compositions of the ophthalmic solution are disclosed in Table 1.
  • the drug product is an isotonic ophthalmic suspension prepared in
  • carboxymethylcellulose sodium and buffer solution pH range from 5.5 to 8.0.
  • the drug particle sizes are reduced to below 40 micron.
  • solubilizer, and preservative agents might be added to enhance functionality of the formulation suspension.
  • the compositions are disclosed in Table 2.
  • the drug product is an isotonic ophthalmic emulsion.
  • the drug is dissolved in the mixture oil phase and emulsifier excipients which is then emulsified and mixed with an aqueous phase with pH range from 5.5 to 8.0.
  • Other viscosity, lubricant, solubilizer, and preservative agents might be added to enhance functionality of the emulsion formulation.
  • Table 3 The compositions are disclosed in Table 3.
  • Citric acid monohydrate Buffer/preservative 0-0.13
  • the drug product is an isotonic sustained release semi-solid formulation.
  • the drug is dissolved and/or suspended in a semi-solid medium with pH range from 5.5 to 8.0.
  • Other viscosity, lubricant, solubilizer, and preservative agents might be added to enhance functionality of the sustained release semi-solid formulation.
  • compositions are disclosed in Table 4.
  • the drug product is a solid implant.
  • the drug is mixed and blended with one or more polymers.
  • the mixture of drug and polymers is melted at a predetermined temperature and extruded into a filament with a predetermined diameter size.
  • the formulation filament is cut into a predetermined size of segment which can be implanted into ocular tissues.
  • Table 5 The compositions are disclosed in Table 5.
  • an example composition for use in the methods according to the invention, may be modified from existing ophthalmically acceptable compositions.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Inorganic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Dispersion Chemistry (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Compositions and methods of using nintedanib for improving the success rate of glaucoma filtration surgery are disclosed herein. Nintedanib can be used alone or in combination with an anti-metabolite drug in a topical or implant eye formulation.

Description

COMPOSITIONS AND METHODS OF USING NINTEDANIB FOR IMPROVING GLAUCOMA SURGERY SUCCESS
CLAIM OF PRIORITY
This application claims the benefit of U. S. Provisional Patent Application Serial No. 62/344,878, filed on June 02, 2016, and U. S. Provisional Patent
Application Serial No. 62/344,870, filed on June 02, 2016, the entire contents of each are hereby incorporated by reference.
TECHNICAL FIELD
The present disclosure relates to ocular compositions comprising nintedanib and methods of use thereof for improving the success rate of glaucoma surgery.
BACKGROUND
Glaucoma refers to a group of eye conditions that damage the optic nerve, which is often caused by an abnormally high pressure in the eye. One way to reduce pressure in an eye with glaucoma is to surgically create a drain in the eye. This type of surgery is called a glaucoma filtration surgery, e.g., trabeculectomy. In glaucoma surgery, a piece of tissue in the drainage angle of the eye is removed, creating an opening. This new opening creates a drain, allowing fluid to drain out of the eye. The eye pressure is reduced because fluid can now drain with relative ease through the new opening through the new opening into a reservoir (bleb) underneath the conjunctiva. The fluid is then absorbed by the body.
As a result of glaucoma filtration surgery, scarring and fibrosis can develop at the surgical site. The scarring and fibrosis often results in a gradual reduction of filtration and loss of control of intraocular pressure. Excess fibrosis is a key factor leading to scar formation and the failure of glaucoma filtration surgery. Current treatments for reducing the failure are still inadequate and need improvements.
SUMMARY
In certain aspects, the disclosure provides a method for improving the success rate of glaucoma surgery (e.g., glaucoma filtration surgery) by administering nintedanib to the eye of a subject in need of such treatment. One aspect features a method for adjunctive treatment associated with glaucoma filtration surgery in a subject comprising administering to a subject in need thereof an effective amount of a composition comprising nintedanib or a pharmaceutically acceptable salt thereof. The method improves the success rate of glaucoma surgery. Glaucoma surgery includes, for example, the classic trabeculectomy method, or a method selected from the group consisting of Trabectome, Gonioscopy-assisted transluminal trabeculectomy, Excimer laser trabeculostomy, and Endoscopic cyclophotocoagulation. The glaucoma surgery performed may also be for implantation of an ocular filtration device, wherein the ocular filtration device is an ocular stent. For example, the ocular filtration device may be selected from the group consisting of an iStent, Hydrus and CyPass microstent.
In some aspects of the methods disclosed herein, the amount of nintedanib administered to the subject is effective to extend the duration of lower IOP, increase either the absolute success rate or the qualified success rate for at least 10 days, at least 90 days, at least 365 days, at least 750 days, or at least 3650 days following surgery; or wherein the amount of nintedanib administered is effective to prolong bleb survival.
In some aspects, the nintedanib composition is administered in the form of topical ocular formulation (e.g., a topical eye drop) or implant. In some examples, the nintedanib is in a topical ocular formulation administered topically to the affected eye. In certain aspect, the concentration of nintedanib in the formulation is from 0.001 % to 10% by weight or by volume the total amount of composition. In certain aspect, the topical ocular formulation is a solution, a suspension or an emulsion. In another aspect, nintedanib is in an implant or semi-solid sustained release formulation injected into the affected eye. In certain aspect, the amount of nintedanib in the implant is from 1 μg to 100 mg.
In certain aspect, the disclosed methods are performed by the combination of nintedanib and an antimetabolite drug. The antimetabolite drug can be, but not limited to, Mitomycin C, 5-Fluorouracil, Floxuridine, Cytarabine, 6-Azauracil, Azathioprine, Methotrexate, Mycophenolate Mofetil, and Thiotepa.
In another aspect, the disclosed methods reduce scar formation in glaucoma surgery by attenuating abnormal vascularity and fibrosis at the surgical site. In certain aspect, the disclosed methods are performed before operation, in conjunction with operation or after operation, to reduce failure in glaucoma surgery. Thus, in some aspects, the amount of nintedanib administered is effective to reduce scar formation at the site of the surgery; In some aspects, the amount nintedanib administered is effective to extend the duration of lower IOP for at least 10 days, at least 365 days, or at least 3650 days following surgery. In some aspects, the amount of nintedanib administered is effective to prolong bleb survival
As used herein, the term "one or more" includes at least one, more suitably, one, two, three, four, five, ten, twenty, fifty, one-hundred, five-hundred, etc., of the item to which "one or more" refers
The term "subject" refers to an animal or human, or to one or more cells derived from an animal or human. Preferably, the subject is a human. Subjects can also include non-human primates. A human subject can be known as a patient.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.
Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims.
DESCRIPTION OF DRAWINGS
Figure 1 is a flow chart demonstrating an exemplary mechanism to reduce excess scar formation and to improve the success rate of glaucoma surgery.
Figure 2 is a graph showing bleb survival following glaucoma filtration surgery in a rabbit model.
Figure 3 is a graph showing intraocular pressure (IOP) following glaucoma filtration surgery in a rabbit model.
Figure 4 is a graph showing absolute success of glaucoma filtration surgery in a clinical study according to the methods disclosed herein.
DETAILED DESCRIPTION Glaucoma is a group of diseases that are characterized by the death of retinal ganglion cells ("RGCs"), specific visual field loss, and optic nerve atrophy.
Glaucoma is a leading cause of blindness in the world. A variety of treatment options, effective to reduce intraocular pressure ("IOP"), are available to control, and, perhaps, to slow, the progression of the disease. Treatment options include, for example, pharmaceutical therapy (i.e., IOP-lowering drugs), laser eye surgery, and/or conventional surgical methods, such as glaucoma filtration surgery (or also known as filtering surgery or trabeculectomy).
Despite the wide usage of topical IOP-lowering drugs in the developed countries, glaucoma surgery is still commonly practiced in other parts of the world, especially for closed-angle glaucoma. Glaucoma surgery has the advantage of low cost over time and doesn't have to deal with compliance issues associated with topical eye drops that need multiple applications per day. The traditional glaucoma filtration surgery and trabeculectomy have high failure rate (Schlunck et al. Exp Eye Res. 2016; 142:76-82) and methods of implanting an ocular filtration device, e.g., a glaucoma drainage device, also have long term failure problems (Amoozgar et al. Curr Opin Ophthalmol. 2016;27(2): 164-9). The failures are due to excessive postoperative wound healing with subsequent fibrosis and scar formation that obstruct drainage. The damage to tissue by surgery often induces pro-inflammation and pro-fibrogenic factors that lead to abnormal extracellular matrix change and fibrosis. Myofibroblast hyper-proliferation induced by these factors subsequently causes excessive fibrosis and scar formation.
The antimetabolite drug, Mitomycin C (MMC) has been administered during or after glaucoma surgery as an anti-scaring agent. Another antimetabolite drug, 5- fluorouracil (5-FU), is also used mainly by local injection during follow-up (Schlunck et al. Exp Eye Res. 2016; 142:76-82). These antimetabolite drugs work by blocking fast proliferating fibroblasts. Their activities are not selective and are known to cause side effects. For example, the anti-cell division activity sometimes causes bleb leakage post-surgery. Better postoperative management of glaucoma surgery is still an unmet medical need.
Due to the multi-factorial causes of scar formation following glaucoma surgery, targeting any single pathway alone may not be sufficient to improve surgery success. The present disclosure improves glaucoma surgery success by administering to the eye a composition with the following key attributes: 1) the composition will inhibit several important pathological pathways simultaneously and these pathways are disclosed below; 2) the composition utilizes small molecule drug(s) as opposed to antibody drugs to achieve more efficient drug delivery to the target tissue; 3) the composition is a topical formulation in the form of either an eye drop or implant for convenient and consistent drug delivery to the site of surgery; and 4) the composition contains nintedanib, which can be used in combination with an antimetabolite drug to achieve additive or synergistic effect in improving the success of glaucoma filtration surgery.
The disclosure provides a method of using a topical formulation (e.g., topical eye drop, implant) comprising nintedanib, before, during or after surgery. Nintedanib meets the requirement of inhibiting vascular endothelial growth factor ("VEGF") receptors ("VEGFR") 1 -3, platelet-derived growth factor receptor ("PDGFR") -a and -β and fibroblast growth factor receptor 2 ("FGFR2") to achieve the needed efficacy.
Without being bound to theory, it is understood that it is important to inhibit all VEGFR members is critical because of the need to block placental growth factor ("PIGF") in addition to VEGF. PIGF only acts on pathologic angiogenesis and inflammation and contributes more to the problems associated with glaucoma surgery (Van Bergen et al. J Cell Mol Med. 2013; 17(12): 1632-43). For glaucoma filtration surgery, the disclosed methods also inhibit FGFR2 due to its function in scar formation. The topical formulation disclosed herein allows for convenient treatment before, during and after surgery. The mechanism for improving glaucoma surgery success rate provided by the present disclosure is summarized in Figure 1, which shows that nintedanib, in a suitable ocular formulation, would simultaneously block signal pathways of the key pathogenic factors involved in excess wound healing, including PIGF, VEGF, PDGF, FGF, and would enhance the success of glaucoma surgery by reducing scar formation.
As used herein, the term "improving glaucoma surgery success" means extending the duration of reduced (i.e., lower) IOP for a period of at least 10 days, at least 90 days, at least 365 days, at least 750 days, or at least 3650 days) following surgery, an increase of IOP-reduction percentage comparing to the pre-surgical baseline over a given period of time (e.g., at least 10 days, at least 90 days, at least 365 days, at least 750 days, or at least 3650 days) after surgery, increase of the absolute (also known as complete) success rate (defined as percent of patients kept within normal IOP range with reduced IOP in relation to the baseline without any glaucoma medication) over a given period of time, increase of qualified success rate (defined as percent of patients kept within normal IOP range with reduced IOP in relation to the baseline with the help of glaucoma medications) over certain period of time (e.g., at least 10 days, at least 90 days, at least 365 days, at least 750 days, or at least 3650 days), improvement of the bleb grade and survival over certain period of time (e.g., at least 10 days, at least 90 days, at least 365 days, at least 750 days, or at least 3650 days).
As used herein, "normal IOP" or "normal IOP range" refers to intraocular pressure in the human eye of between about 5 mm Hg to about 22 mm Hg, or about 10 mm Hg to about 21 mm Hg.
The terms "treatment", "treating", "treat" and the like are used herein to generally refer to obtaining a desired pharmacologic and/or physiologic effect. The effect can be prophylactic in terms of completely or partially preventing a disease or symptom(s) thereof and/or may be therapeutic in terms of a partial or complete stabilization or cure for a disease and/or adverse effect attributable to the disease. The term "treatment" encompasses any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing the disease and/or symptom(s) from occurring in a subject who may be predisposed to the disease or symptom but has not yet been diagnosed as having it; (b) inhibiting the disease and/or symptom(s), i.e., arresting their development; or (c) relieving the disease symptom(s), i.e., causing regression of the disease and/or symptom(s). Those in need of treatment include those already inflicted (e.g., those with high IOP, those with an infection, etc.) as well as those in which prevention is desired (e.g., those with increased susceptibility to glaucoma, those suspected of having high IOP, etc.).
Nintedanib {Methyl (3Z)-3-{[(4-{methyl[(4-methylpiperazin-l-yl) acetyl] amino} phenyl)amino] (phenyl)methylidene}-2-oxo-2,3-dihydro-lH-indole-6- carboxylate}is a kinase inhibitor as described herein. Nintedanib inhibits primarily receptor tyrosine kinases including, for example vascular endothelial growth factor receptor (VEGFR 1-3), platelet-derived growth factor receptor (PDGFR a and β), fibroblast growth factor receptor (FGFR 1-4).
Formulations and Dosing Regimen The methods described herein include the manufacture and use of
pharmaceutical compositions, which include compounds identified by a method described herein as active ingredients. Also included are the pharmaceutical compositions themselves.
Pharmaceutical compositions typically include pharmaceutically acceptable excipients. As used herein the language "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" includes saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
The phrase "pharmaceutically acceptable salt" as used herein means those salts of a compound of interest that are safe and effective for administration to a mammal and that possess the desired biological activity. Pharmaceutically acceptable acid salts include, but are not limited to hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, I 0 isonicotinate, carbonate, bicarbonate, acetate, lactate, salicylate, citrate, tartrate, propionate, butyrate, pyruvate, oxalate, malonate, pantothenate, bitartarte, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, thanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., I, I'rnethylene-bis-(2-hydroxy-3-naphthoate )) salts. Suitable base salts include, but are not limited to, 15 aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, bismuth, and diethanolamine salts.
Methods of formulating suitable pharmaceutical compositions are known in the art, see, e.g., Remington: The Science and Practice of Pharmacy, 21st ed., 2005; and the books in the series Drugs and the Pharmaceutical Sciences: a Series of Textbooks and Monographs (Dekker, NY). For example, solutions, suspensions, , creams, ointments, Gels, gel-forming liquid, suspension containing liposomes or micelles, spray orformulation, or emulsions used for ophthalmic application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents; antioxidants; chelating agents; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. Pharmaceutical compositions suitable for injectable use can include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. It should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying, which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
In one embodiment, the therapeutic compounds are prepared with carriers that will protect the therapeutic compounds against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polygly colic acid, collagen, polyorthoesters, and polylactic acid. Such formulations can be prepared using standard techniques, or obtained commercially. The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.
Compositions and formulations of nintedanib, can be administered topically (e.g., as a topical ocular formulation) or as an injection of semi-solid formulation or solid implant, or by any other suitable methods known in the art. While it is possible to use the agent disclosed herein for therapy as is, it may be preferable to administer the agent as a pharmaceutical formulation, e.g., in admixture with a suitable pharmaceutical excipient, diluent, or carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Pharmaceutical formulations include at least one active compound, in association with a pharmaceutically acceptable excipient, diluent, and/or carrier.
The pharmaceutical composition disclosed herein may include a
"therapeutically effective amount" of an agent described herein. Such effective amounts can be determined based on the effect of the administered agent, or the combinatorial effect of agents if more than one agent is used. A therapeutically effective amount of an agent may also vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the compound to elicit a desired response in the individual, e.g., amelioration of at least one disorder parameter or amelioration of at least one symptom of the disorder. A therapeutically effective amount is also one in which any toxic or detrimental effects of the composition are outweighed by the therapeutically beneficial effects.
Effective doses of the compositions of the present disclosure, for the treatment of conditions vary depending upon many different factors, including means of administration, target site, physiological state of the subject, whether the subject is human or an animal, other medications administered, and whether treatment is prophylactic or therapeutic. Treatment dosages can be titrated using routine methods known to those of skill in the art to optimize safety and efficacy.
In some instances, the topical ocular formulation is a solution, a suspension, , creams, ointments, gels, gel-forming liquid, suspension containing liposomes or micelles, spray formulation, or an emulsion. In some cases, the topical ocular formulation also includes one or more pharmaceutically acceptable excipients selected from stabilizers, surfactants, polymer base carriers, gelling agents, organic co-solvents, pH active components, osmotic active components and with or without preservatives. In some cases, the sustained release semi-solid formulation, sustained release solid formulation or ocular implant is injected into the affected eye. In some embodiments, the sustained release semi-solid formulation, sustained release solid formulation or ocular implant further comprises a pharmaceutically acceptable excipient. In some cases, the sustained release semi-solid formulation, sustained release solid formulation or ocular implant includes a multikinase inhibitor, the antimetabolite, or combination thereof; and a biodegradable polymer selected from polylactic acid (PLA), poly gly colic acid (PLGA) and polylactic acid poly gly colic acid copolymers.
Administration of a composition or formulation can be once a day, twice a day, three times a day, four times a day or more often. Frequency may be decreased during a treatment maintenance phase of the treatment, e.g., once every second or third day instead of every day or twice a day. The dose and the administration frequency can be adjusted based on the judgment of the treating physician, for example, taking into account the clinical signs, pathological signs and clinical and subclinical symptoms of a disease of the conditions treated with the present methods, as well as the patient's clinical history.
It will be appreciated that the amount of an agent disclosed herein required for use in treatment will vary with the route of administration, the nature of the condition for which treatment is required, and the age, body weight and condition of the patient, and will be ultimately at the discretion of the attendant physician. Compositions will typically contain an effective amount of nintedanib. Preliminary doses can be determined according to animal tests, and the scaling of dosages for human administration can be performed according to art-accepted practices.
Length of treatment, i.e., number of days, will be readily determined by a physician treating the subject; however, the number of days of treatment may range from about 1 day to about 365 days. As provided by the present methods, the efficacy of treatment can be monitored during the course of treatment to determine whether the treatment has been successful, or whether additional (or modified) treatment is necessary.
Dosage, toxicity and therapeutic efficacy of the therapeutic compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). Dosage forms for nintedanib can be readily determined by the ordinarily skilled artisan, and can e.g., be obtained in animal models and in clinical studies reported in the literatures, for determining dosage, safety and efficacy according to standard methods known in the art. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition.
Compositions for use in the present methods may include nintedanib at a concentration of 0.001% to 10% by weight or by volume the total amount of composition. For example, an aqueous composition comprises 0.001%, 0.01%, 0.1%, 0.5%, 1.0%, 1.5%, 2.0%, 5.0% or up to 10% nintedanib.
As will be familiar to those skilled in the art, administration to the eye of an aqueous solution may be in the form of "drop" or number of drops (e.g. of nintedanib solution) from a dropper or pipette or other dedicated sterile devices. Such drops will typically be up to 50 microliters in volume, but maybe smaller e.g. less than 10 microliters.
EXAMPLES
The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.
Example 1: Rabbit Glaucoma Surgery Model.
The rabbit glaucoma surgery model is used to illustrate use of the presently disclosed methods for improving the success of glaucoma filtration surgery. Specially, an established rabbit model of glaucoma filtration surgery would be used to study the effects of nintedanib 0.2% solution on the wound-healing events after surgery. The surgical procedure is as described in Wong et al. (Wong et al. Invest Ophthalmol Vis Sci. 2003; 44(3): 1097-1103). Briefly, a partial thickness 8-0 silk corneal traction suture is placed superiorly, and the eye pulled down. A fornix based conjunctival flap is raised, after which a blunt dissection of the subconjunctival space is performed of approximately 5 mm along the limbus and 8 mm posteriorly. A microvitreoretinal (MVR) blade is used to make a partial-thickness scleral incision 3 to 4 mm behind the limbus, and a scleral tunnel to the corneal stroma is fashioned. A 22 -gauge, 25 -mm intravenous cannula (Venflon 2; Beckton Dickinson, Oxford, UK) is passed through a scleral tunnel anteriorly until the cannula needle is visible in the clear cornea. Entry into the anterior chamber is made with a cannular needle, which is then withdrawn as the cannula is advanced to the mid-pupillary area. The cannula is trimmed and beveled at its scleral end so that it protrudes 1 mm from the insertion point, and a 10-0 nylon suture is placed to fix the tube to the scleral surface. The conjunctival incision is closed with two interrupted sutures and a central, mattress-type 10-0 nylon suture attached to a needle (B/V 100-4; Ethicon) to give a water-tight closure. One drop each of guttae chloramphenicol and Betnesol-N (Glaxo Wellcome, Uxbridge, UK) ointment is instilled at the end of surgery.
Twenty female New Zealand White rabbits (2-2.4 kg, 12-14 weeks old; Charles River) would be acclimatized for 5 days before the experiments start.
Glaucoma surgery would be performed on the left eye as described. After surgery, the rabbits would be arranged into two groups and one group would be treated with vehicle and another with nintedanib 0.2% solution. Treatments would begin immediately after surgery and the treatment would be TID for 2 weeks. The survival of the bleb formed by the surgery and the intraocular pressure (IOP) would be followed for 28 days. Histological analysis of the scar tissue would be performed at the end of the study.
Results
Surgery success outcome would be significantly prolonged in the nintedanib group compared with the vehicle group. Figure 2 provides a graph showing the survival curve of the bleb after surgery. As shown in Figure 2, the nintedanib group would show a substantially prolonged bleb survival comparing to the vehicle group. By the end of study on day 28, no bleb would survive in the vehicle group while most of the bleb would survive in the nintedanib group. Figure 3 is a graph showing the IOP curve during the follow up period after the surgery. IOP remained low (i.e., below 20 mm- » -in the nintedanib group and increased gradually in the vehicle group. The difference would be statistically significant. In addition to bleb survival and IOP change, histological analysis of scar tissue at the surgical site would show less scar tissue in the nintedanib group than the vehicle group.
The results from this experiment would indicate that the nintedanib 0.2% solution increases the success of glaucoma surgery (i.e., prolonged bleb survival, extended duration of lower IOP following surgery and/or reduced fibrosis/scarring).
Example 2: Topical Ocular Formulations of Nintedanib as Adjunct Therapy to Glaucoma Filtration Surgery Topical nintedanib 0.2% as adjunct therapy to increase success of
trabeculectomy in a clinical study. A randomized, double-masked, placebo-controlled, 12-month experimental trial to test the effects of topical nintedanib 0.2% on the success rate of trabeculectomy. The study design would be as described by
Vandewalle et al (Vandewalle et al. Br J Ophthalmol. 2014, Jan; 98(l):73-8).
Patients with medically uncontrolled open-angle glaucoma scheduled for a primary trabeculectomy would be enrolled and randomized to receive one drop TID of either nintedanib or placebo solutions. The treatment would start immediately after surgery and would last for a month. Approximately 150 patients would be enrolled in the study.
Surgeries would be performed under general or retrobulbar anaesthesia by experienced surgeons using a modified Moorfields technique. IOP would be measured by Goldmann applanation tonometry. Two measurements were taken by masked observers and averaged to determine the mean IOP if two values were within 2 mm Hg. A third measurement would be taken if the difference between the first two determinations is >2 mm Hg.
Patients would be examined on day 1; at weeks 1, 2, and 4; and at months 3, 6, and 12 after trabeculectomy. All patients would go through a comprehensive ophthalmic examination that included measurements of best-corrected visual acuity, slit-lamp examination including a Seidel test, IOP measurement, and fundus biomicroscopy with a 90-diopter lens. The number of postoperative IOP-lowering medications, intra- and postoperative complications, and surgical interventions would also be recorded.
Absolute success would be the primary endpoint and is defined as intraocular pressure (IOP) <21 mm Hg and >5 mm Hg with at least 20% reduction from baseline and no loss of light perception.
Results
IOP would be effectively reduced in both nintedanib and placebo groups at the 12-month visit when compared to baseline. The absolute success rate of glaucoma surgery, i.e., maintaining IOP of less than about 20 mm Hg for more than 12 months after surgery, would be higher in the nintedanib group vs the placebo group as shown in Figure 4. At time points after 6 months, the differences would be statistically significant. Example 3: Formulations
Nintedanib Ophthalmic Solution
The drug product is an isotonic ophthalmic solution prepared in 2-hydroxypropyl beta cyclodextrin or other similar cyclodextrins, and buffer solution, pH range from 5.5 to 8.0. Other viscosity, lubricant, preservative agents might be added to enhance functionality of the formulation. The compositions of the ophthalmic solution are disclosed in Table 1.
Table 1 Nintedanib Ophthalmic Solution
Figure imgf000016_0001
Functions Concentration Range
Ingredients
(%w/v)
Sodium phosphate Buffer Agent 0 - 0.43 monobasic monohydrate
Sodium phosphate dibasic Buffer Agent 0 - 0.8 heptahydrate
Boric acid Buffer Agent 0 - 0.6
Sodium borate, Buffer Agent 0 - 0.045 decahydrate
Citric acid, monohydrate Buffer Agent/preservative 0 - 0.13
Sodium citrate, dihydrate Buffer Agent/preservative 0 - 0.45
Glycerin Tonicity Agent 0 - 2.2
Sodium chloride Tonicity Agent 0 - 0.83
IN Sodium hydroxide pH Adjustment
IN Hydrochloric acid pH 5.5 - 8.0
Water for injection Vehicle Q.S. to 100
Nintedanib Ophthalmic Suspension
The drug product is an isotonic ophthalmic suspension prepared in
carboxymethylcellulose sodium and buffer solution, pH range from 5.5 to 8.0. The drug particle sizes are reduced to below 40 micron. Other viscosity, lubricant,
solubilizer, and preservative agents might be added to enhance functionality of the formulation suspension. The compositions are disclosed in Table 2.
Nintedanib Ophthalmic Suspension
Figure imgf000017_0001
Functions Concentration Range
Ingredients
(%w/v)
Polyvinyl alcohol Viscosity /Lubrication Agent 0-1.5
Hypromellose Lubricant/dry eye relief 0- 1
Carbomers Lubricant/dry eye relief 0-0.5
Carmellose sodium Lubricant/dry eye relief 0-1
Sodium hyaluronate Lubricant/dry eye relief 0-1.5
Polyethylene glycol 400 Lubricant/dry eye relief 0-0.4
Propylene glycol Lubricant/dry eye relief 0-0.6
2-hydroxypropyl beta Solubilizer 0- 10 cyclodextrin
Sulfobutyl-beta- Solubilizer 0- 10 cyclodextrin
Randomly methylated beta- Solubilizer 0-5 cyclodextrin
a-cyclodextrin Solubilizer 0-4 β-cyclodextrin Solubilizer 0- 1 γ-cyclodextrin Solubilizer 0- 1
Poloxamer 188, or 237, or Solubilizer/lubricant 0-5 407
Polysorbate 80 Solubilizer/lubricant/surfactant 0-1
Edetate disodium Chelating Agent/Preservative 0-0.01
Benzalkonium chloride Preservative 0 - 0.02
Sodium phosphate Buffer Agent 0-0.43 monobasic monohydrate
Sodium phosphate dibasic Buffer Agent 0-0.8 heptahydrate
Boric acid Buffer Agent 0-0.6
Sodium borate, Buffer Agent 0-0.045 decahydrate
Citric acid, monohydrate Buffer Agent/preservative 0-0.13
Sodium citrate, dihydrate Buffer Agent/preservative 0-0.45
Glycerin Tonicity Agent 0-2.2
Sodium chloride Tonicity Agent 0-0.83
IN Sodium hydroxide pH Adjustment
IN Hydrochloric acid pH 5.5 -8.0
Water for injection Vehicle Q.S. to 100
Nintedanib Ophthalmic Emulsion The drug product is an isotonic ophthalmic emulsion. The drug is dissolved in the mixture oil phase and emulsifier excipients which is then emulsified and mixed with an aqueous phase with pH range from 5.5 to 8.0. Other viscosity, lubricant, solubilizer, and preservative agents might be added to enhance functionality of the emulsion formulation. The compositions are disclosed in Table 3.
Nintedanib Ophthalmic Emulsion
Functions Concentration
Ingredients
(% w/w)
CBT-001 (Nintedanib free Active Pharmaceutical Ingredient 0.001 - 10 base)
Castor oil Oil solvent 0-1.25
Polyoxyl-40-Stearate Emulsifier 0 - 0.25
Polysorbate 80 Solubilizer/Emulsifier/Surfactant 0-1
Sulfobutyl--cyclodextrin Solubilizer 0-5
2-Hydroxypropyl-beta- Solubilizer 0-5 cyclodextrin
Randomly methylated beta- Solubilizer 0-5 cyclodextrin
a-cyclodextrin Solubilizer 0-4 β-cyclodextrin Solubilizer 0- 1 γ-cyclodextrin Solubilizer 0- 1
Glycerin Tonicity Agent 0-2.2
Sodium Chloride Tonicity Agent 0-0.83
Pemulen TR2 Viscosity Agent 0-0.1
Sodium Viscosity Agent 0-0.5 carboxymethylcellulose
Polyvinyl alcohol Viscosity /Lubrication Agent 0-1.5
Hypromellose Lubricant/dry eye relief 0-1
Carbomers Lubricant/dry eye relief 0-0.5
Carmellose sodium Lubricant/dry eye relief 0-1
Sodium hyaluronate Lubricant/dry eye relief 0-1.5
Polyethylene glycol 400 Lubricant/dry eye relief 0-0.4
Propylene glycol Lubricant/dry eye relief 0-0.6
Poloxamer 188, or 237, or Solubilizer/lubricant 0-5 407
Boric acid Buffer 0-0.6
Sodium borate, Buffer 0-0.045 decahydrate
Citric acid, monohydrate Buffer/preservative 0-0.13
Sodium citrate, dihydrate Buffer/preservative 0 - 0.45
Sodium phosphate, Buffer 0-0.43 monobasic monohydrate
Sodium phosphate dibasic Buffer 0-0.8 heptahydrate Functions Concentration
Ingredients
(% w/w)
IN & 5N Sodium pH Adjustment pH 5.5 - 8.0 hydroxide
IN Hydrochloric acid
Water for injection Aqueous Vehicle Q.S. 100
Nintedanib Sustained Release Semi-Solid Formulation
The drug product is an isotonic sustained release semi-solid formulation. The drug is dissolved and/or suspended in a semi-solid medium with pH range from 5.5 to 8.0. Other viscosity, lubricant, solubilizer, and preservative agents might be added to enhance functionality of the sustained release semi-solid formulation. The
compositions are disclosed in Table 4.
Table 4 Sustained Release Semi-Solid Formulation
Figure imgf000022_0001
Nintedanib Sustained Release Implants
The drug product is a solid implant. The drug is mixed and blended with one or more polymers. The mixture of drug and polymers is melted at a predetermined temperature and extruded into a filament with a predetermined diameter size. The formulation filament is cut into a predetermined size of segment which can be implanted into ocular tissues. The compositions are disclosed in Table 5.
Table 5 Sustained Release Implants
Figure imgf000023_0001
Without limitation, an example composition, for use in the methods according to the invention, may be modified from existing ophthalmically acceptable compositions.
OTHER EMBODIMENTS
It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

What is claimed is:
1. A method for improving success rate of glaucoma filtration surgery, comprising administering to an eye of a subject in need thereof a therapeutically effective amount of nintedanib or a pharmaceutically acceptable salt thereof.
2. The method of claim 1, wherein nintedanib is administered in the form of topical eye drop or implant.
3. The method of claim 1, wherein the amount of nintedanib administered is effective to reduce scar formation at the site of the surgery.
4. The method of claim 1, wherein the amount of nintedanib administered is effective to extend the duration of lower IOP, increase either the absolute success rate or the qualified success rate for at least 10 days, at least 90 days, at least 365 days, at least 750 days, or at least 3650 days following surgery; or wherein the amount of nintedanib administered is effective to prolong bleb survival.
5. The method of claim 1, wherein nintedanib is administered in the form of either a semi-solid or solid sustained-release implant injected into the affected eye.
6. The method of claim 1, wherein the topical ocular formulation is solution, suspension, , creams, ointments, gels, gel-forming liquid, suspension containing liposomes or micelles, spray formulation, or emulsion.
7. The method of claim 1, wherein the treatment is performed before, during or after operation.
8. The method of claim 1, wherein the glaucoma filtration surgery is performed using the classic trabeculectomy or a method selected from the group consisting of Trabectome, Gonioscopy-assisted transluminal trabeculotomy, Excimer laser trabeculostomy, and Endoscopic cyclophotocoagulation.
9. The method of claim 1, wherein the glaucoma surgery performed is for implanting an ocular filtration device.
10. The method of claim 9, wherein the ocular filtration device is an ocular stent.
11. The method of claim 9, wherein the ocular filtration device is selected from the group consisting of an iStent, Hydrus and CyPass microstent.
12. The method of claims 1, wherein nintedanib is administered in combination with a cell-proliferation-inhibiting antimetabolite drug.
13. The method of claim 12, wherein the antimetabolite drug is selected from the group consisting of Mitomycin C, 5-Fluorouracil, Floxuridine, Cytarabine, 6-Azauracil, Azathioprine, Methotrexate, Mycophenolate Mofetil, and Thiotepa.
14. A method of adjunctive treatment associated with glaucoma filtration surgery in a subject, the method comprising administering to a subject in need thereof an effective amount of a composition comprising nintedanib or a pharmaceutically acceptable salt thereof.
15. The method of claim 14, wherein composition is administered in the form of topical eye drop or implant.
16. The method of claim 14, wherein the composition contains an amount of nintedanib effective to reduce scar formation at the site of the surgery.
17. The method of claim 14, wherein the composition contains an amount of nintedanib effective to extend the duration of lower IOP, or increase either the absolute or the qualified success rate defined above, for at least 10 days, or at least 365 days, or at least 3650 days following surgery.
18. The method of claim 15, wherein the amount of nintedanib administered is effective to prolong bleb survival.
19. The method of claim 14, wherein nintedanib is administer to the eye before, during or after glaucoma filtration surgery.
20. The method of claim 14, wherein nintedanib is in either a semi-solid or solid sustained-release implant is inj ected into the affected eye.
21. The method of claim 14, wherein the topical ocular formulation is solution, suspension or emulsion.
22. The method of claim 14, wherein the glaucoma filtration surgery is performed using the classic trabeculectomy or a method selected from the group consisting of Trabectome, Gonioscopy-assisted transluminal trabeculotomy, Excimer laser trabeculostomy, and Endoscopic cyclophotocoagulation.
23. The method of claim 14, wherein the glaucoma surgery performed is for implanting an ocular filtration device.
24. The method of claim 23, wherein the ocular filtration device is an ocular stent.
25. The method of claim 23, wherein the ocular filtration device is selected from the group consisting of an iStent, Hydrus and CyPass microstent.
26. The method of claims 1, wherein nintedanib is administered in combination with a cell-proliferation-inhibiting antimetabolite drug.
27. The method of claim 26, wherein the antimetabolite drug is selected from the group consisting of Mitomycin C, 5-Fluorouracil, Floxuridine, Cytarabine, 6-Azauracil, Azathioprine, Methotrexate, Mycophenolate Mofetil, and Thiotepa.
PCT/US2017/034792 2016-06-02 2017-05-26 Compositions and methods of using nintedanib for improving glaucoma surgery success Ceased WO2017210130A1 (en)

Priority Applications (14)

Application Number Priority Date Filing Date Title
KR1020237003530A KR102657707B1 (en) 2016-06-02 2017-05-26 Compositions and methods of using nintedanib for improving glaucoma surgery success
EP17807295.5A EP3463225B1 (en) 2016-06-02 2017-05-26 Nintedanib for reducing scar formation at the site of glaucoma filtration surgery
CN201780029923.1A CN109561985B (en) 2016-06-02 2017-05-26 Compositions and methods for improving the success of glaucoma surgery using nintedanib
CA3025325A CA3025325A1 (en) 2016-06-02 2017-05-26 Compositions and methods of using nintedanib for improving glaucoma surgery success
MX2018014868A MX2018014868A (en) 2016-06-02 2017-05-26 Compositions and methods of using nintedanib for improving glaucoma surgery success.
JP2019515766A JP7079243B2 (en) 2016-06-02 2017-05-26 Compositions and Methods Using Nintedanib to Improve the Success Rate of Glaucoma Surgery
AU2017274195A AU2017274195B2 (en) 2016-06-02 2017-05-26 Compositions and methods of using nintedanib for improving glaucoma surgery success
KR1020247011786A KR20240052865A (en) 2016-06-02 2017-05-26 Compositions and methods of using nintedanib for improving glaucoma surgery success
BR112018074450-6A BR112018074450A2 (en) 2016-06-02 2017-05-26 compositions and methods for using nintedanib to improve the success of glaucoma surgery
KR1020187037794A KR102496234B1 (en) 2016-06-02 2017-05-26 Compositions and methods of using nintedanib to improve glaucoma surgery success
US16/131,945 US10335408B2 (en) 2016-06-02 2018-09-14 Compositions and methods of using nintedanib for improving glaucoma surgery success
US16/439,469 US10688092B2 (en) 2016-06-02 2019-06-12 Compositions and methods of using nintedanib for improving glaucoma surgery success
AU2022204216A AU2022204216B2 (en) 2016-06-02 2022-06-16 Compositions and methods of using nintedanib for improving glaucoma surgery success
AU2025200273A AU2025200273A1 (en) 2016-06-02 2025-01-14 Compositions and methods of using nintedanib for improving glaucoma surgery success

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201662344878P 2016-06-02 2016-06-02
US201662344870P 2016-06-02 2016-06-02
US62/344,878 2016-06-02
US62/344,870 2016-06-02

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US16/131,945 Continuation US10335408B2 (en) 2016-06-02 2018-09-14 Compositions and methods of using nintedanib for improving glaucoma surgery success

Publications (1)

Publication Number Publication Date
WO2017210130A1 true WO2017210130A1 (en) 2017-12-07

Family

ID=60477780

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/US2017/034795 Ceased WO2017210132A1 (en) 2016-06-02 2017-05-26 Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization
PCT/US2017/034792 Ceased WO2017210130A1 (en) 2016-06-02 2017-05-26 Compositions and methods of using nintedanib for improving glaucoma surgery success

Family Applications Before (1)

Application Number Title Priority Date Filing Date
PCT/US2017/034795 Ceased WO2017210132A1 (en) 2016-06-02 2017-05-26 Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization

Country Status (10)

Country Link
US (5) US11246864B2 (en)
EP (3) EP4248971A3 (en)
JP (4) JP7079243B2 (en)
KR (5) KR102496234B1 (en)
CN (3) CN109475506A (en)
AU (6) AU2017274195B2 (en)
BR (2) BR112018074454A2 (en)
CA (2) CA3026118A1 (en)
MX (4) MX389460B (en)
WO (2) WO2017210132A1 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019524880A (en) * 2017-05-01 2019-09-05 アイビバ バイオファーマ インコーポレイテッド Multikinase inhibitor
US20190290643A1 (en) * 2016-06-02 2019-09-26 Cloudbreak Therapeutics, Llc Compositions and methods of using nintedanib for improving glaucoma surgery success
US10980741B2 (en) 2015-06-06 2021-04-20 Cloudbreak Therapeutics, Llc Compositions and methods for treating pterygium recurrence
JP2021534153A (en) * 2018-08-15 2021-12-09 アイビバ バイオファーマ インコーポレイテッド VEGF and TGF Beta Multikinase Inhibitors and Their Use

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190388407A1 (en) 2017-02-12 2019-12-26 Aiviva Biopharma, Inc. Multikinase inhibitors of vegf and tfg beta and uses thereof
WO2021142298A1 (en) * 2020-01-08 2021-07-15 Radiance Therapeutics, Inc. Methods, systems, and compositions for maintaining functioning drainage blebs
GB201714392D0 (en) 2017-09-07 2017-10-25 Marsteller Laurence Methods and devices for treating glaucoma
US12605563B2 (en) 2017-09-07 2026-04-21 Radiance Therapeutics, Inc. System for brachytherapy
AU2019272871B2 (en) * 2018-05-25 2025-02-27 Ads Therapeutics Llc A composition for treating ocular hyperemia and a method for treating ocular hyperemia with the same
WO2020047146A1 (en) * 2018-08-28 2020-03-05 Cloudbreak Therapeutics, Llc Emulsion formulations of multikinase inhibitors
EP3856478A4 (en) * 2018-09-25 2022-06-08 Aldeyra Therapeutics, Inc. FORMULATIONS FOR THE TREATMENT OF DRY EYE DISEASE
JP2022502160A (en) 2018-09-28 2022-01-11 ラディアンス セラピューティクス、インコーポレイテッド Methods, systems, and compositions for maintaining functioning drainage vesicles associated with minimally invasive microscleral incision.
CN113556994A (en) 2018-11-29 2021-10-26 光辉疗法公司 Ophthalmic brachytherapy system and apparatus using beta radiation
BR112021026662A2 (en) * 2019-09-10 2022-04-12 Cloudbreak Therapeutics Llc Methods to alleviate pterygium-associated concern about the appearance of the eye
CN110787127A (en) * 2019-12-11 2020-02-14 龚雁 Eye temperature-sensitive gel and preparation method thereof
PT3884929T (en) 2020-03-25 2023-08-09 Ocular Therapeutix Inc Ocular implant containing a tyrosine kinase inhibitor
EP4171507A1 (en) * 2020-06-30 2023-05-03 Oculis SA Preparation of solid cyclodextrin complexes for ophthalmic active pharmaceutical ingredient delivery
KR102769064B1 (en) * 2020-12-30 2025-02-19 한국과학기술연구원 Composition for enhancing cancer treatment effect containing nintedanib and use thereof
USD1076086S1 (en) 2021-11-23 2025-05-20 Radiance Therapeutics, Inc. Opthalmic brachytherapy device
USD1076085S1 (en) 2021-11-23 2025-05-20 Radiance Therapeutics, Inc. Opthalmic brachytherapy device
CN116251186B (en) * 2021-12-09 2025-04-25 成都瑞沐生物医药科技有限公司 A tyrosine kinase inhibitor ophthalmic preparation and its preparation method and use
PE20260040A1 (en) 2023-04-11 2026-01-09 Ocular Therapeutix Inc OCULAR IMPLANT CONTAINING A TYROSINE KINASE INHIBITOR
MX2023009955A (en) * 2023-08-24 2025-03-07 Sophia Holdings S A De C V The present invention relates to ophthalmic pharmaceutical compositions containing dorzolamide, methods for their preparation and use thereof.

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120315282A1 (en) 2011-06-03 2012-12-13 Xoma Technology Ltd. Antibodies Specific for TGF-Beta
US20150258120A1 (en) * 2012-11-08 2015-09-17 Clearside Biomedical, Inc. Methods and devices for the treatment of ocular diseases in human subjects
US20150265469A1 (en) * 2012-10-11 2015-09-24 The Regents Of The University Of Colorado, A Body Corporate Ocular filtration devices, systems and methods
WO2016029191A2 (en) 2014-08-22 2016-02-25 Auckland Uniservices Limited Channel modulators

Family Cites Families (62)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2198692T3 (en) 1997-02-14 2004-02-01 Kissei Pharmaceutical Co., Ltd. MEDICATIONS INHIBITING THE PROGRESS OF PTERIGION AND ITS POST-OPERATIONAL FREQUENCY.
PE20010306A1 (en) 1999-07-02 2001-03-29 Agouron Pharma INDAZOLE COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM USEFUL FOR THE INHIBITION OF PROTEIN KINASE
UA75054C2 (en) 1999-10-13 2006-03-15 Бьорінгер Інгельхайм Фарма Гмбх & Ко. Кг Substituted in position 6 indolinones, producing and use thereof as medicament
US7442372B2 (en) * 2003-08-29 2008-10-28 Biomarin Pharmaceutical Inc. Delivery of therapeutic compounds to the brain and other tissues
CA2572223C (en) 2004-06-25 2014-08-12 The Johns Hopkins University Angiogenesis inhibitors
WO2006020979A2 (en) 2004-08-13 2006-02-23 Yale University Factor vii conjugates for selectively treating neovascularization disorders
US9993558B2 (en) * 2004-10-01 2018-06-12 Ramscor, Inc. Sustained release eye drop formulations
US7893040B2 (en) 2005-07-22 2011-02-22 Oculis Ehf Cyclodextrin nanotechnology for ophthalmic drug delivery
US20080003219A1 (en) 2005-09-26 2008-01-03 Minu, L.L.C. Delivery of an ocular agent
WO2007038453A2 (en) 2005-09-26 2007-04-05 Advanced Ocular Systems Limited Use of an anti-vascular endothelial growth factor (vegf) agent to ameliorate inflammation
US8558002B2 (en) 2006-11-16 2013-10-15 Allergan, Inc. Sulfoximines as kinase inhibitors
NZ580126A (en) 2007-04-05 2012-03-30 Pfizer Prod Inc Crystalline forms of 6- [2- (methylcarbamoyl) phenylsulfanyl] -3-e- [2- (pyridin-2-yl) ethenyl] indazole suitable for the treatment of abnormal cell growth in mammals
US11078262B2 (en) 2007-04-30 2021-08-03 Allergan, Inc. High viscosity macromolecular compositions for treating ocular conditions
RU2351298C1 (en) 2007-11-27 2009-04-10 Государственное учреждение "УФИМСКИЙ НАУЧНО-ИССЛЕДОВАТЕЛЬСКИЙ ИНСТИТУТ ГЛАЗНЫХ БОЛЕЗНЕЙ" Академии наук Республики Башкортостан (УфНИИ ГБ АН РБ) Method of prevention of pterygium relapse
UA104590C2 (en) 2008-06-06 2014-02-25 Берингер Ингельхайм Интернациональ Гмбх Capsule pharmaceutical dosage form comprising a suspension formulation of an indolinone derivative
UA107560C2 (en) 2008-06-06 2015-01-26 PHARMACEUTICAL FORM FOR THE IMMEDIATE RELEASE OF INDOLINON DERIVATIVES
US20100098772A1 (en) 2008-10-21 2010-04-22 Allergan, Inc. Drug delivery systems and methods for treating neovascularization
US20100185564A1 (en) 2009-01-21 2010-07-22 Mccormick & Company, Inc. Method and questionnaire for measuring consumer emotions associated with products
US20100247606A1 (en) 2009-03-25 2010-09-30 Allergan, Inc. Intraocular sustained release drug delivery systems and methods for treating ocular conditions
UY33164A (en) 2010-01-06 2011-08-31 Glaxo Wellcome Mfg Pte Ltd TREATMENT METHOD
CN102821753A (en) 2010-01-22 2012-12-12 阿勒根公司 Intracameral Sustained Release Therapeutic Implants
US20140057908A1 (en) * 2010-09-27 2014-02-27 Exelixis, Inc. Method of Treating Cancer
CN102018686B (en) 2010-12-16 2012-12-05 浙江大学医学院附属邵逸夫医院 Mitomycin-containing film agent and preparation method thereof
JP2014505689A (en) * 2011-01-13 2014-03-06 ノバルティス アーゲー BACE-2 inhibitor for the treatment of metabolic disorders
KR20140048218A (en) 2011-06-28 2014-04-23 바이엘 헬스케어 엘엘씨 Topical ophthalmological pharmaceutical composition containing regorafenib
CN103764118A (en) 2011-06-28 2014-04-30 拜尔健康护理有限责任公司 Topical ophthalmic composition containing sorafenib
WO2013004766A1 (en) * 2011-07-04 2013-01-10 Ferrari Giulio Nk-1 receptor antagonists for treating corneal neovascularisation
EP2802314B1 (en) 2012-01-13 2020-11-25 XSpray Microparticles AB A method for producing stable, amorphous hybrid nanoparticles comprising at least one protein kinase inhibitor and at least one polymeric stabilizing and matrix- forming component.
CN103212075B (en) 2012-01-19 2017-06-27 成都康弘生物科技有限公司 A kind of eye drops containing VEGF antagonist
WO2013126799A1 (en) 2012-02-22 2013-08-29 Trustees Of Tufts College Compositions and methods for ocular delivery of a therapeutic agent
CN111700879A (en) 2012-05-03 2020-09-25 卡拉制药公司 Drug nanoparticles exhibiting enhanced mucosal transport
WO2013188283A1 (en) 2012-06-12 2013-12-19 Bayer Healthcare Llc Topical ophthalmological pharmaceutical composition containing sunitinib
HK1204563A1 (en) 2012-06-25 2015-11-27 Bayer Healthcare Llc Topical ophthalmological pharmaceutical composition containing pazopanib
US20150165028A1 (en) 2012-06-25 2015-06-18 Bayer Healthcare Llc Topical ophthalmological pharmaceutical composition containing cediranib
HK1204564A1 (en) 2012-06-25 2015-11-27 Bayer Healthcare Llc Topical ophthalmological pharmaceutical composition containing axitinib
EP2919802A4 (en) 2012-11-15 2016-09-14 Univ Tufts METHODS, COMPOSITIONS AND KITS FOR TREATING, MODULATING OR PREVENTING ANGIOGENESIS OR OCULAR FIBROSIS IN A SUBJECT USING A GALECTIN INHIBITOR
US8747852B1 (en) 2012-12-28 2014-06-10 Randal Tanh Hoang Pham Methods of treating pterygium
US20160038760A1 (en) 2013-03-14 2016-02-11 Massachusetts Eye And Ear Infirmary Conjunctival diseases
AU2014248460B2 (en) 2013-04-01 2019-04-11 Allergan, Inc. Microsphere drug delivery system for sustained intraocular release
BR112015027762A2 (en) 2013-05-03 2017-08-29 Clearside Biomedical Inc APPLIANCE AND METHODS FOR OCULAR INJECTION
US20140378401A1 (en) 2013-06-21 2014-12-25 Gnt, Llc Ophthalmic Lipophilic and Hydrophilic Drug Delivery Vehicle Formulations
CA2936239A1 (en) 2014-01-16 2015-07-23 Ontogenesis, Llc Compositions and methods for the treatment of intraocular neovascularization and/or leakage
CN104448300B (en) 2014-12-09 2017-01-11 西安医学院 Low-molecular-weight L-polyglutamine-mitomycin C as well as synthesis method and applications thereof
CA2974702C (en) 2015-01-26 2023-10-10 University Of Washington Compositions and methods for treating toxoplasmosis, cryptosporidiosis and other apicomplexan protozoan related diseases
KR20260025887A (en) 2015-06-06 2026-02-24 클라우드브레이크 테라퓨틱스, 엘엘씨 Compositions and methods for treating pterygium
PE20180252A1 (en) 2015-06-09 2018-02-02 Bayer Pharma AG ALOSTERIC POSITIVE MODULATORS OF THE MUSCARINIC RECEIVER M2
TWI700085B (en) 2015-06-22 2020-08-01 新源生物科技股份有限公司 Use of ophthalmic formulations of tyrosine kinase inhibitors
EP3324902B1 (en) 2015-07-22 2024-12-18 Incept, LLC Coated punctal plug
CN108295072A (en) * 2015-12-09 2018-07-20 瑞阳(苏州)生物科技有限公司 Nintedanib prevents the purposes of eye disease
CN106902117A (en) * 2015-12-23 2017-06-30 瑞阳(苏州)生物科技有限公司 A kind of medicine for preventing or treating CNV to be formed
WO2017120600A1 (en) * 2016-01-08 2017-07-13 Clearside Biomedical, Inc. Compositions and methods of treating wet age-related macular degeneration
CN108602879A (en) 2016-02-04 2018-09-28 倪劲松 Antibody-drug synergistic action technique for treating disease
AU2017274195B2 (en) 2016-06-02 2022-04-07 Ads Therapeutics Llc Compositions and methods of using nintedanib for improving glaucoma surgery success
US11278546B2 (en) 2016-07-22 2022-03-22 Aiviva Biopharma, Inc. Multikinase inhibitors and uses in ocular fibrosis
EP3515444A4 (en) 2016-09-26 2020-06-03 Reyoung (Suzhou) Biology Science & Technology Co., Ltd COMPOSITION FOR THE TREATMENT OF EYE DISEASES, AND METHODS OF USE AND METHODS OF MAKING
US11510931B2 (en) 2016-09-28 2022-11-29 Medicon Pharmaceuticals, Inc. Compositions and methods for treating ophthalmic conditions
CN110072849A (en) 2017-03-14 2019-07-30 新源生物科技股份有限公司 3-Z-[1-(4-(N-((4-Methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-idene Crystal form of methyl]-6-methoxycarbonyl-2-indolinone
AU2019272871B2 (en) 2018-05-25 2025-02-27 Ads Therapeutics Llc A composition for treating ocular hyperemia and a method for treating ocular hyperemia with the same
CN110664757B (en) 2018-11-19 2022-08-02 成都瑞沐生物医药科技有限公司 Nanocrystalline eye drop, preparation method and application thereof
BR112021026662A2 (en) 2019-09-10 2022-04-12 Cloudbreak Therapeutics Llc Methods to alleviate pterygium-associated concern about the appearance of the eye
CA3171479A1 (en) 2020-02-19 2021-08-26 Clearside Biomedical, Inc. Compositions comprising axitinib and methods of treating ocular disorders
CN116251186B (en) 2021-12-09 2025-04-25 成都瑞沐生物医药科技有限公司 A tyrosine kinase inhibitor ophthalmic preparation and its preparation method and use

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120315282A1 (en) 2011-06-03 2012-12-13 Xoma Technology Ltd. Antibodies Specific for TGF-Beta
US20150265469A1 (en) * 2012-10-11 2015-09-24 The Regents Of The University Of Colorado, A Body Corporate Ocular filtration devices, systems and methods
US20150258120A1 (en) * 2012-11-08 2015-09-17 Clearside Biomedical, Inc. Methods and devices for the treatment of ocular diseases in human subjects
WO2016029191A2 (en) 2014-08-22 2016-02-25 Auckland Uniservices Limited Channel modulators

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy", 2005
AMOOZGAR ET AL., CURR OPIN OPHTHALMOL, vol. 27, no. 2, 2016, pages 164 - 9
MASOUMPOUR MB ET AL., THE OPEN OPHTHALMOLOGY JOURNAL, vol. 10, no. 1, 29 February 2016 (2016-02-29), pages 68 - 85
O'CONNOR J ET AL., JOURNAL OF CURRENT GLAUCOMA PRACTICE, vol. 8, no. 2, 1 August 2014 (2014-08-01), pages 46 - 53
SCHLUNCK ET AL., EXP EYE RES, vol. 142, 2016, pages 76 - 82
VAN BERGEN ET AL., J CELL MOL MED., vol. 17, no. 12, 2013, pages 1632 - 43
VANDEWALLE ET AL., BR J OPHTHALMOL, vol. 98, no. 1, January 2014 (2014-01-01), pages 73 - 8
WOLLIN L ET AL., EUROPEAN RESPIRATORY JOURNAL, vol. 45, no. 5, 30 May 2015 (2015-05-30), pages 1434 - 1445
WONG ET AL., INVEST OPHTHALMOL VIS SCI, vol. 44, no. 3, 2003, pages 1097 - 1103

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10980741B2 (en) 2015-06-06 2021-04-20 Cloudbreak Therapeutics, Llc Compositions and methods for treating pterygium recurrence
US12186424B2 (en) 2015-06-06 2025-01-07 Cloudbreak Therapeutics, Llc Compositions and methods for treating pterygium recurrence
US20190290643A1 (en) * 2016-06-02 2019-09-26 Cloudbreak Therapeutics, Llc Compositions and methods of using nintedanib for improving glaucoma surgery success
US10688092B2 (en) * 2016-06-02 2020-06-23 Cloudbreak Therapeutics, Llc Compositions and methods of using nintedanib for improving glaucoma surgery success
US11246864B2 (en) 2016-06-02 2022-02-15 Ads Therapeutics Llc Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization
US11911379B2 (en) 2016-06-02 2024-02-27 Ads Therapeutics Llc Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization
US12491183B2 (en) 2016-06-02 2025-12-09 Ads Therapeutics Llc Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization
US11278546B2 (en) 2016-07-22 2022-03-22 Aiviva Biopharma, Inc. Multikinase inhibitors and uses in ocular fibrosis
JP2019524880A (en) * 2017-05-01 2019-09-05 アイビバ バイオファーマ インコーポレイテッド Multikinase inhibitor
EP3619232A4 (en) * 2017-05-01 2021-01-13 AiViva Biopharma, Inc. MULTIKINASE INHIBITORS AND THEIR USES IN OCULAR FIBROSIS
EP3619232B1 (en) 2017-05-01 2023-06-07 AiViva Biopharma, Inc. Multikinase inhibitors and uses in ocular fibrosis
JP2021534153A (en) * 2018-08-15 2021-12-09 アイビバ バイオファーマ インコーポレイテッド VEGF and TGF Beta Multikinase Inhibitors and Their Use

Also Published As

Publication number Publication date
EP3463315B1 (en) 2023-06-14
US20190290643A1 (en) 2019-09-26
AU2022202629B2 (en) 2024-06-13
US11911379B2 (en) 2024-02-27
US20220125783A1 (en) 2022-04-28
KR20240052865A (en) 2024-04-23
JP7475395B2 (en) 2024-04-26
JP2019518790A (en) 2019-07-04
KR20240049636A (en) 2024-04-16
EP3463315A1 (en) 2019-04-10
AU2025200273A1 (en) 2025-01-30
US20190015409A1 (en) 2019-01-17
CN109561985A (en) 2019-04-02
CA3025325A1 (en) 2017-12-07
AU2017274197A1 (en) 2018-12-06
AU2022202629A1 (en) 2022-05-19
EP3463315A4 (en) 2020-01-15
JP2022116191A (en) 2022-08-09
BR112018074454A2 (en) 2019-03-19
US10688092B2 (en) 2020-06-23
MX2024007658A (en) 2024-07-04
KR20220080222A (en) 2022-06-14
AU2024219639A1 (en) 2024-10-03
US20200323844A1 (en) 2020-10-15
JP7079243B2 (en) 2022-06-01
MX2018014869A (en) 2019-09-13
US10335408B2 (en) 2019-07-02
US11246864B2 (en) 2022-02-15
EP3463225A4 (en) 2020-03-11
EP4248971A2 (en) 2023-09-27
CN119656170A (en) 2025-03-21
BR112018074450A2 (en) 2019-03-19
AU2017274195A1 (en) 2018-12-13
CA3026118A1 (en) 2017-12-07
KR20190032300A (en) 2019-03-27
AU2017274195B2 (en) 2022-04-07
US12491183B2 (en) 2025-12-09
JP2024083587A (en) 2024-06-21
EP3463225B1 (en) 2026-02-11
JP2019517578A (en) 2019-06-24
KR102657707B1 (en) 2024-04-15
EP3463225A1 (en) 2019-04-10
EP4248971A3 (en) 2024-02-14
EP3463315C0 (en) 2023-06-14
MX2022000754A (en) 2022-02-14
AU2017274197B2 (en) 2022-02-10
WO2017210132A1 (en) 2017-12-07
KR102496234B1 (en) 2023-02-06
MX2018014868A (en) 2019-09-13
AU2022204216A1 (en) 2022-07-14
CN109561985B (en) 2022-03-04
CN109475506A (en) 2019-03-15
JP7082115B2 (en) 2022-06-07
KR20190040935A (en) 2019-04-19
US20240238279A1 (en) 2024-07-18
MX389460B (en) 2025-03-20
KR20230023812A (en) 2023-02-17
KR102408596B1 (en) 2022-06-13
AU2022204216B2 (en) 2024-10-17

Similar Documents

Publication Publication Date Title
AU2022204216B2 (en) Compositions and methods of using nintedanib for improving glaucoma surgery success
HK40100601A (en) Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization
HK40000005A (en) Compositions and methods of using nintedanib for improving glaucoma surgery success
HK40000005B (en) Compositions and methods of using nintedanib for improving glaucoma surgery success
KR102961448B1 (en) Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization
HK40000009A (en) Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization

Legal Events

Date Code Title Description
ENP Entry into the national phase

Ref document number: 3025325

Country of ref document: CA

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17807295

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2019515766

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112018074450

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 2017274195

Country of ref document: AU

Date of ref document: 20170526

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 20187037794

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2017807295

Country of ref document: EP

Effective date: 20190102

ENP Entry into the national phase

Ref document number: 112018074450

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20181127

WWR Wipo information: refused in national office

Ref document number: 1020247011786

Country of ref document: KR

WWR Wipo information: refused in national office

Ref document number: 1020247011786

Country of ref document: KR

WWC Wipo information: continuation of processing after refusal or withdrawal

Ref document number: 1020247011786

Country of ref document: KR

WWG Wipo information: grant in national office

Ref document number: 2017807295

Country of ref document: EP